Epoxidation catalysts

ABSTRACT

The present invention generally relates to methods for the synthesis of catalysts, including epoxidation catalysts, and related compounds and catalyst compositions. Embodiments described herein may provide efficient processes for providing catalysts (e.g., epoxidation catalysts) in large quantities and using simplified methods.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant No. R01GM072566 awarded by the National Institutes of Health. The governmenthas certain rights in this invention.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/037,060, filed Feb. 28, 2011, which claims priority under 35 U.S.C.§119(e) to U.S. Provisional Application Ser. No. 61/309,067, filed Mar.1, 2010, the contents of which applications are incorporated herein byreference in their entire for all purposes.

FIELD OF THE INVENTION

The present invention generally relates to methods for the synthesis ofcatalysts, including epoxidation catalysts, and related compositions.

BACKGROUND OF THE INVENTION

Optically active epoxides provide useful building blocks in thesynthesis of many biologically active compounds, and much research hasbeen conducted on practical, efficient methods for the synthesis of suchepoxides. For example, numerous catalysts have been developed to performepoxidation reactions, in which an alkene is converted to an epoxide byaddition of one oxygen atom to a carbon-carbon double bond. Inparticular, the “Shi Epoxidation,” is an enantioselective epoxidationmethod developed by Prof. Yian Shi and coworkers, which utilizes Shicatalyst 1, shown below.

While the Shi Epoxidation method has been shown to be effective forenantioselective epoxidation reactions, to date, Shi catalyst 1 can onlybe produced in large quantities as one enantiomer. The absence of theavailability of the enantiomer of Shi catalyst 1 has hindered the morewidespread use of the Shi Epoxidation.

SUMMARY OF THE INVENTION

The present invention provides methods for synthesizing a catalyst. Inone set of embodiments, the method comprises reacting a compound ofFormula (I),

wherein:

R¹ and R² can be the same or different and each can be hydrogen, alkyl,or aryl, provided that when one of R¹ and R² is hydrogen, the other isalkyl or aryl;

R³ is a protecting group;

R⁴ is a protecting group that can be removed in the presence of an acid;and

R⁵, R⁶, R⁷, and R⁸ can be the same or different and each can behydrogen, alkyl, or aryl, to produce a compound of Formula (II),

The present invention also relates to compositions comprising a compoundhaving a structure as in Formula (I):

wherein:

R¹ and R² can be the same or different and each can be hydrogen, alkyl,or aryl, provided that when one of R¹ and R² is hydrogen, the other isalkyl or aryl;

R³ is a protecting group;

R⁴ is a protecting group that can be removed in the presence of an acid;and

R⁵, R⁶, R⁷, and R⁸ can be the same or different and each can behydrogen, alkyl, or aryl.

The present invention also relates to compositions comprising a compoundhaving a structure as in Formula (II):

wherein:

R¹ and R² can be the same or different and each can be hydrogen, alkyl,or aryl, provided that when one of R¹ and R² is hydrogen, the other isalkyl or aryl; and

R⁵, R⁶, R⁷, and R⁸ can be the same or different and each can behydrogen, alkyl, or aryl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the preparation of compound 2, a TBS-protecteddihydroxyacetone.

FIG. 1B shows the synthesis of the ent-Shi ketone.

FIG. 2 shows a proposed mechanism for synthesis of an intermediatecompound in the synthesis of the ent-Shi ketone.

Other aspects, embodiments and features of the invention will becomeapparent from the following detailed description when considered inconjunction with the accompanying drawings. The accompanying figures areschematic and are not intended to be drawn to scale. For purposes ofclarity, not every component is labeled in every figure, nor is everycomponent of each embodiment of the invention shown where illustrationis not necessary to allow those of ordinary skill in the art tounderstand the invention. All patent applications and patentsincorporated herein by reference are incorporated by reference in theirentirety. In case of conflict, the present specification, includingdefinitions, will control.

DETAILED DESCRIPTION

The present invention generally relates to methods for the synthesis ofcatalysts, including epoxidation catalysts, and related compounds andcatalyst compositions. Some embodiments provide methods for synthesizinglarge amounts (e.g., greater than 10 grams) of a catalyst compositionthat may otherwise be difficult to obtain using known methods. In someembodiments, compounds and intermediates useful in the synthesis ofcatalysts are provided. Embodiments described herein may provideefficient processes for providing catalysts (e.g., epoxidationcatalysts) in large quantities and using simplified methods.

Methods for synthesizing the compounds and catalyst compositionsdescribed herein are provided. In some cases, the method may comprisereacting an intermediate molecule to produce a compound or catalyst, asdescribed herein. In some cases, the intermediate molecule may be acompound comprising at least one ketal group and/or at least oneprotecting group. Other intermediate molecules are described herein,including the Examples. Methods described herein may involve one or morechemical transformations, which may be performed sequentially and/orsimultaneously. For example, the method may comprise reacting a compoundin the presence of a chemical reagent (e.g., acid), wherein multiplechemical transformations may occur in a single reaction step. Those ofordinary skill in the art would be able to select the appropriate set(s)of reaction conditions (e.g., concentration, temperature, pressure,reaction time, solvents, etc.) suitable for use in a particularapplication. In some cases, the method may further comprise isolatingand/or purifying the compound and/or catalyst, for example, bychromatography (e.g., column chromatography, HPLC), crystallization,precipitation, distillation, filtration, solvent extraction, and thelike. The method may also comprise characterization of the compoundand/or catalyst by mass spectrometry, NMR, and the like.

Some embodiments relate to the synthesis of the following compound,

also known as the “ent-Shi ketone” catalyst, which is the enantiomer ofa commercially available catalyst known as “Shi ketone.” The ent-Shiketone catalyst has been shown to be an effective catalyst forenantioselective epoxidation reactions. In some embodiments, methods forsynthesizing the ent-Shi ketone catalyst, as described herein, mayinclude fewer synthetic steps and may produce the ent-Shi ketonecatalyst in higher yields, relative to known methods. In some cases, theent-Shi ketone catalyst may advantageously be produced in relativelylarge amounts, when performing a single iteration of a synthetic scheme.For example, carrying out the synthetic scheme shown in FIG. 1B one timemay produce the ent-Shi ketone catalyst in relatively large quantities(e.g., greater than 10 grams). In some embodiments, the method mayproduce a catalyst (e.g., the ent-Shi catalyst) in an amount of 10 gramsor greater, 20 grams or greater, 30 grams or greater, 40 grams orgreater, 50 grams or greater, 60 grams or greater, 70 grams or greater,80 grams or greater, 90 grams or greater, 100 grams or greater, 150grams or greater, or, in some cases, 200 grams or greater, based upon asingle run of a particular synthetic scheme. In one set of embodiments,the ent-Shi ketone catalyst may be produced in quantities ranging fromabout 50 grams to about 60 grams, based upon a single run of aparticular synthetic scheme.

Some embodiments involve reacting a compound of Formula (I),

wherein:

R¹ and R² can be the same or different and each can be hydrogen, alkyl,or aryl, provided that when one of R¹ and R² is hydrogen, the other isalkyl or aryl;

R³ is a protecting group;

R⁴ is a protecting group that can be removed in the presence of an acid;and

R⁵, R⁶, R⁷, and R⁸ can be the same or different and each can behydrogen, alkyl, or aryl, to produce a compound of Formula (II),

In some embodiments, R¹ and R² are alkyl; and R⁵, R⁶, R⁷, and R⁸ areeach hydrogen.

In one set of embodiments, the compound of Formula (I) has thestructure,

In one set of embodiments, the compound of Formula (II) has thestructure,

In some embodiments, the compound of Formula (I) may include at leastone protecting group. For example, R³ and R⁴ may each comprise asilicon-containing protecting group. In some embodiments, the protectinggroup is trimethylsilyl (TMS), tributylsilyl (TBS),tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS),triisopropylsilyl (TIPS), [2-(trimethylsilyl)ethoxy]methyl (SEM),trimethylsilyl triflate, triethylsilyl triflate, or tri-t-butylsilyltriflate. In one set of embodiments, the protecting group istributylsilyl (TBS). In some cases, the protecting group may be capableof being removed in the presence of an acid.

The phrase “protecting group” as used herein refers to temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

In some embodiments, conversion of a compound of Formula (I) to acompound of Formula (II) may be performed in a one-pot reaction. Theterm “one-pot” reaction is known in the art and refers to a chemicalreaction which can produce a product in one step which may otherwisehave required a multiple-step synthesis. One-pot procedures mayeliminate the need for isolation (e.g., purification) of intermediatesand additional synthetic steps while reducing the production of wastematerials (e.g., solvents, impurities). Additionally, the time and costrequired to synthesize such compounds can be reduced. For example, oneor more chemical transformations may occur in a single reaction vesselto convert of a compound of Formula (I) to a compound of Formula (II),as described more fully below.

In some embodiments, the method may involve exposure of a compound ofFormula (I) to an acid. As used herein, an “acid” refers to any speciescapable of acting as a source of at least one proton. Examples of acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,hydrofluoric acid, hydroiodic acid, hypochloric acid, chloric acid,perchloric acid, periodic acid, sulfuric acid, fluorosulfuric acid,nitric acid, phosphoric acid, hexafluorophosphoric acid, chromic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, trifluoromethanesulfonic acid, nitric acid,acetic acid, citric acid, formic acid, and the like. In someembodiments, the acid may be perchloric acid (HClO₄).

The acid may be provided as an aqueous solution comprising at least 1%,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, or, in some cases, at least 90%acid. In some embodiments, the acid may be added to the reaction mixtureas a solution comprising about 50% to about 80% acid, about 60% to about80% acid, or, about 70% to about 80% acid. In some embodiments, the acidmay be added to the reaction mixture as a solution comprising 70% acid.

The compound of Formula (I) may be exposed to the acid under reactionconditions suitable for use in a particular application. In someembodiments, the reaction mixture may be maintained at any temperaturefrom about −78° C. to about 200° C. In some embodiments, the acid may beadded to the reaction mixture at relatively lower temperatures. Forexample, the reaction mixture may be maintained at any temperature fromabout −78° C. to about room temperature. In some embodiments, thereaction mixture may be maintained at about room temperature or lower,at about 15° C. or lower, at about 10° C. or lower, at about 5° C. orlower, or, at about 0° C. or lower. In one set of embodiments, thereaction mixture may be maintained at about 0° C.

Exposure of a compound of Formula (I) to an acid may result in one ormore chemical transformations, including addition of a nucleophile to acarbonyl, removal/addition of protecting group(s), isomerization ofprotecting group(s), and the like. For example, exposing compound 4 toperchloric acid results in transformation of compound 4 to compound 5.(FIG. 1B) Without wishing to be bound by theory, FIG. 2 shows a proposedmechanism for conversion of compound 4 to compound 5, involving multiplechemical transformations upon exposure to compound 4 to an acid. In somecases, the compound may undergo acid-catalyzed isomerization, such thata protecting group (e.g., cyclic ketal) may moved to a different portionof the compound, as shown in step (a) of FIG. 2. For example, the cyclicketal of compound 4 may be fully removed from compound 4 upon exposureto acid, and a new cyclic ketal may be formed at a different location ofcompound 4. Alternatively, the cyclic ketal in compound 4 may bepartially removed from compound 4 (e.g., only one carbon-oxygen bond ofthe cyclic ketal may be cleaved) and may migrate to a different locationof compound 4, upon exposure to acid. Upon isomerization of the cyclicketal, the compound may then cyclize via addition of hydroxyl group tothe carbonyl, as shown in step (b) of FIG. 2. Subsequent removal and/oraddition of protecting groups at various locations may then producecompound 5, as shown in steps (c)-(e) of FIG. 2.

In some cases, the method may involve the subsequent step ofneutralizing the acid. This may be performed, for example, by exposingthe reaction mixture to a base. Bases suitable for use in the inventioninclude those having sufficient pKa values to neutralize (e.g.,deprotonate) an acidic reagent present within the reaction mixture. Ingeneral, a variety of bases may be used in practice of the presentinvention. Examples of bases include, but are not limited to, alkoxidessuch as sodium t-butoxide, an alkali metal amide such as sodium amide,lithium diisopropylamide or an alkali metal bis(trialkylsilyl)amidessuch as lithium bis(trimethylsilyl)amide or sodiumbis(trimethylsilyl)amide, a tertiary amine (e.g. triethylamine,trimethylamine, Et(i-Pr)₂N, Cy₂MeN, 4-(dimethylamino)pyridine (DMAP),2,6-lutadine, N-methylpyrrolidine (NMP), quinuclidine, and the like),1,5-diazabicycl[4.3.0]non-5-ene (DBN),1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), ammonium salts (e.g., ammoniumhydroxide), alkali and alkaline earth carbonates, alkali and alkalineearth bicarbonates, alkali and alkaline earth hydroxides, alkali andalkaline earth hydrides, (e.g. NaH, LiH, KH, K₂CO₃, Na₂CO₃, Tl₂CO₃,Cs₂CO₃, K(Ot-Bu), Li(Ot-Bu), Na(Ot-Bu) K(OPh), Na(OPh)), and the like.In some embodiments, a solution of ammonium hydroxide may be added tothe reaction mixture to neutralize, for example, HClO₄.

Other suitable bases include quinoline, optionally substituted withalkyl or aryl groups, isoquinoline, optionally substituted with alkyl oraryl groups, imidazole, optionally substituted with alkyl or arylgroups, thiazole, optionally substituted with alkyl or aryl groups, andoxazole, optionally substituted with alkyl or aryl groups. In the abovecompounds, preferred alkyl substituents may be C₁₋₅ alkyl groups andpreferred aryl substituents may be C₆₋₂₀ aryl groups, such as phenyl,substituted phenyl, naphthyl, phenanthryl, and the like. The base may beadded in solid form, or as a solution comprising a base (e.g., anaqueous solution). For example, the acid may be neutralized by exposureto an ammonium hydroxide solution.

In some cases, the method may comprise a protection or deprotectionreaction. For example, the compound of Formula (I) may be exposed to aprotecting group precursor, which may interaction with a portion of thecompound to produce a compound comprising a protecting group. In somecases, the compound of Formula (I) may comprise at least one protectinggroup and may be exposed to conditions under which the protecting groupmay be at least partially removed. In some embodiments, the protectinggroup may be removed from the compound. In some embodiments, theprotecting group may be partially removed from the compound. Forexample, the protecting group may be attached to the compound via atleast two bonds, and one of the bonds may be cleaved during adeprotection step. Some embodiments may involve migration of aprotecting group from one location of the compound to another, differentlocation of the compound.

In some cases the protection or deprotection reaction may be performedin the absence of additional chemical transformations. In someembodiments, the protection or deprotection reaction may be performedsimultaneously with another chemical transformation. For example, acompound of Formula (I) may be exposed to an acid and a protecting groupprecursor at the same time, and may undergo both removal/addition of aprotecting group and addition of a nucleophile to a carbonyl.

Some embodiments involve exposure of a compound of Formula (I) to aspecies capable of forming an acetal or a ketal as a protecting group.As used herein, the terms “acetal” and “ketal” are given their ordinarymeaning in the art and refer to carbonyl-protecting groups having theformula,

wherein R^(a), R^(b), and R^(c) are carbon-containing groups, R^(d) ishydrogen in the case of an acetal, and R^(d) is a carbon-containinggroup in the case of a ketal. In some cases, the species may be capableof forming a cyclic acetal or a cyclic ketal, i.e., where R^(a) andR^(b) are joined together to form a ring. In some embodiments, acetalsmay be produced by reacting an aldehyde species with an alcohol. In someembodiments, ketals may be produced by reacting a ketone species with analcohol.

In some embodiments, the compound of Formula (I) may comprise at leastone hydroxyl group capable of forming an acetal or a ketal upon exposureto an aldehyde species or a ketone species. For example, the compoundmay comprise two hydroxyl groups, each attached to adjacent atoms of thecompound (e.g., a vicinal diol), which may react with a ketone speciesto form a cyclic ketal. In some embodiments, the ketone species may beacetone. As described herein, some embodiments may involveacid-catalyzed isomerization of a cyclic ketal.

In some embodiments, the compound of Formula (I) may be exposed toconditions suitable to remove one or more protecting groups. Forexample, the compound may comprise a silicon-containing protecting groupand may be exposed to a fluoride-containing species capable of removingthe silicon-containing protecting group from the compound. Examples offluoride-containing species include, but are not limited to, sodiumfluoride (NaF) and tetra-n-butylammonium fluoride (TBAF). In some cases,the compound may comprise a TBS group, which may then be removed uponexposure to, for example, TBAF.

In one set of embodiments, the act of reacting a compound of Formula (I)comprises (i) exposure to HClO₄ and acetone; (ii) exposure to ammoniumhydroxide solution; and (iii) exposure to tetra-n-butylammonium fluoride(TBAF).

The method may further comprise exposing the compound of Formula (II) toan oxidant. As used herein, the terms “oxidant” or “oxidizing agent” aregiven their ordinary meaning in the art and refer to a species capableof oxidizing or increasing the oxidation number of a substrate. In someembodiments, the oxidant may be comprise a transition metal. Forexample, the oxidant may comprise ruthenium. Examples of oxidantsinclude halogens (e.g., iodine), peroxides, sulfoxides, ozone, osmiumtetroxide, ruthenium(III) trichloride, chlorite, chlorate, perchlorate,hexavalent chromium compounds, nitric acid, nitrous oxide, permanganatesalts, and the like.

In one set of embodiments, the compound of Formula (II) is oxidized toproduce the ent-Shi catalyst, i.e., a compound having the structure,

In some embodiments, the method may further comprising synthesizing acompound of Formula (I). In some embodiments, the compound may besynthesized via an aldol reaction. In some embodiments, the compound maybe synthesized via an asymmetric aldol reaction. The method may involveperforming an aldol reaction between an aldehyde species having theformula,

wherein R¹ and R² can be the same or different and each can be hydrogen,alkyl, or aryl, provided that when one of R¹ and R² is hydrogen, theother is alkyl or aryl; and R⁵ and R⁶ can be the same or different andeach can be hydrogen, alkyl, or aryl, and a carbonyl species having theformula,

wherein R³ is a protecting group;

R⁴ is a protecting group that can be removed in the presence of an acid;and

R⁷ and R⁸ can be the same or different and each can be hydrogen, alkyl,or aryl.

In some embodiments, the aldehyde species has the following structure,

In some embodiments, the carbonyl species has the following structure,

The aldol reaction may be performed under conditions suitable for use ina particular application. In some embodiments, the aldol reaction may beperformed in the presence of one or more asymmetric (e.g. chiral)species capable of enhancing the formation of a particular desiredproduct. For example, the aldol reaction may be performed in thepresence of a chiral catalyst, chiral auxiliary, and/or chiralsubstrates. Those of ordinary skill in the art would be able to selectthe appropriate chiral species to produce a particular, desired product(e.g., syn aldol product, anti aldol product). In some embodiments, asyn aldol product may be the desired product. In some embodiments, ananti aldol product may be the desired product. In an illustrativeembodiment, an asymmetric aldol reaction may be performed in thepresence of O-tert-butyl-L-threonine.

The aldol reaction may be performed in the presence of one or moresolvents, including organic solvents, aqueous solvents, and combinationsthereof. In some embodiments, the solvent may be a polar aproticsolvent. Examples of polar aprotic solvents includeN-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide,and dimethyl sulfoxide, and the like.

In some embodiments, the aldol reaction mixture may be maintained at anytemperature from about −78° C. to about 200° C. For example, the aldolreaction mixture may be maintained at any temperature from about −78° C.to about 50° C. In some embodiments, the aldol reaction mixture may bemaintained at about 50° C. or lower, at about 30° C. or lower, at about10° C. or lower, at about 5° C. or lower, or, at about 0° C. or lower.In one set of embodiments, the reaction mixture may be maintained atabout room temperature.

Upon reaction, the contrast agent may be subjected to one or morepurification steps. Purification and isolation may be performed usingmethods known to those skilled in the art, including separationtechniques like chromatography, or combinations of various separationtechniques as are known the art. In one embodiment, high performanceliquid chromatography (HPLC) may be used with a solvent, or mixture ofsolvents, as the eluent, to recover the product. In some cases, theeluent may include a mixture of water and acetonitrile, such as a 45:55water:acetonitrile mixture. The content of water may vary from, forexample, about 1% to about 50%. In some cases, HPLC may be performedusing a C18 column

Any of the compounds or intermediates described herein product may befurther processed using one or more purification techniques.Purification and isolation may be performed using methods known to thoseskilled in the art, including separation techniques like chromatography,recrystallization, distillation, or combinations of various separationtechniques as are known the art. In some cases, the compound orintermediate may be purified using column chromatography. Any solvent,or mixture of solvents, may be uses the eluent to recover the product.In some cases, the eluent may include hexane, ethyl acetate, and/or amixture of hexane and ethyl acetate, such as a 1:1 hexane:ethyl acetatemixture, a 2:1 hexane:ethyl acetate mixture, a 20:1 hexane:ethyl acetatemixture, or the like.

In some embodiments, a compound or intermediate may be purified usingrecrystallization, a process which may be repeated until desired purityof product is obtained. In one embodiment, the compound or intermediateis recrystallized at least once, two times, three times, or four or moretimes to achieve the desired level of purity. For example, the compoundor intermediate may be obtained at purities of greater than or equal to50%, 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99.8%. Recrystallization maybe achieved using a single solvent, or a combination of solvents. Insome cases, recrystallization is achieved by dissolving the compound orintermediate in a solvent such as hexane at elevated temperatures, andthen cooling the solution to produce a precipitate. For example, thecompound may be recrystallized from hexane.

FIG. 1B shows an illustrative embodiment, wherein ent-Shi ketone 6 (theent-Shi ketone catalyst) is synthesized from L-ascorbic acid. As shownin FIG. 1B, L-ascorbic acid may be converted to (S)-glyceraldehyde 3,using the methods described in U.S. Publication No. 2007/0073068, thecontents of which are incorporated herein by reference in its entiretyfor all purposes. An asymmetric aldol reaction may then be performedbetween (S)-glyceraldehyde 3 and compound 2, in the presence ofO-tert-butyl-L-threonine and NMP, to produce aldol compound 4. Compound4 may then be reacted as described herein. In one set of embodiments,the act of reacting compound 4 comprises (i) exposure to HClO₄ andacetone; (ii) exposure to ammonium hydroxide solution; and (iii)exposure to tetra-n-butylammonium fluoride (TBAF), to produce compound5, which may then be oxidized to produce ent-Shi ketone 6.

In some embodiments, the ent-Shi ketone catalyst may be synthesized from(S)-glyceraldehyde in three steps with an overall yield of at least 10%,at least 20%, or at least 30%. In some cases, the ent-Shi ketonecatalyst may be synthesized from (S)-glyceraldehyde in three steps withan overall yield of about 35%. In some embodiments, the ent-Shi ketonecatalyst may be synthesized from L-ascorbic acid in six steps with anoverall yield of at least 5%, at least 10%, or at least 13%. In somecases, the ent-Shi ketone catalyst may be synthesized from L-ascorbicacid in six steps with an overall yield of about 13.2%.

Some embodiments provide novel compounds or intermediates. In some case,compositions are provided comprising a compound having a structure as inFormula (I):

wherein:

R¹ and R² can be the same or different and each can be hydrogen, alkyl,or aryl, provided that when one of R¹ and R² is hydrogen, the other isalkyl or aryl;

R³ is a protecting group;

R⁴ is a protecting group that can be removed in the presence of an acid;and

R⁵, R⁶, R⁷, and R⁸ can be the same or different and each can behydrogen, alkyl, or aryl.

In some embodiments, the compound has the following structure,

In some embodiments, R³ and R⁴ each comprise a silicon-containingprotecting group, such as trimethylsilyl (TMS), tributylsilyl (TBS),tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS)triisopropylsilyl (TIPS), [2-(trimethylsilyl)ethoxy]methyl (SEM),trimethylsilyl triflate, triethylsilyl triflate, or tri-t-butylsilyltriflate.

In some embodiments, the compound of Formula (I) has the structure,

In other embodiments, compositions comprising a compound having astructure as in Formula (II):

wherein:

R¹ and R² can be the same or different and each can be hydrogen, alkyl,or aryl, provided that when one of R¹ and R² is hydrogen, the other isalkyl or aryl; and

R⁵, R⁶, R⁷, and R⁸ can be the same or different and each can behydrogen, alkyl, or aryl, are provided.

In one set of embodiments, the compound has the following structure,

Suitable silicon compounds or silicon-containing compounds which may beused in methods of the invention may include those which are capable offorming a covalent bond with an oxygen atom. For example, thesilicon-containing compound may form a covalent bond with an oxygen atomto form a silyl ether. In some embodiments, the silicon compound has theformula R³SiX, wherein R³ can be optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, and X can be halide, triflate, or thelike. In some embodiments, the silicon compound is trimethylsilyl (TMS),tributylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS),tert-butyldimethylsilyl (TBDMS) triisopropylsilyl (TIPS),[2-(trimethylsilyl)ethoxy]methyl (SEM), trimethylsilyl triflate,triethylsilyl triflate, or tri-t-butylsilyl triflate. In someembodiments, the

Solvents which may be used in methods of the invention include inertsolvents such as benzene, p-cresol, toluene, xylene, diethyl ether,glycol monomethyl or dimethyl ether, petroleum ether, hexane,cyclohexane, methylene chloride, chloroform, carbon tetrachloride,dioxane, tetrahydrofuran (THF), dimethyl sulfoxide, dimethylformamide,hexamethyl-phosphoric triamide, ethyl acetate, pyridine, triethylamine,picoline, mixtures thereof, or the like. Preferred solvents may includebenzene, toluene, xylene, ether, hexane, petroleum ether, methylenechloride, chloroform, or tetrahydrofuran. In a particular embodiment,toluene is the preferred solvent.

The products which may be produced by methods of the present inventionmay undergo further reaction(s) to afford desired derivatives thereof.Such permissible derivatization reactions can be carried out inaccordance with conventional procedures known in the art. For example,potential derivatization reactions include cleavage of theoxygen-silicon bond of a silyl ether of an allylic alcohol to afford theallylic alcohol. Suitable reagents which can cleave an oxygen-siliconbond to deprotect an alcohol are known, such as tetrabutylammoniumfluoride (TBAF), for example.

As used herein, the term “reacting” refers to the forming of a bondbetween two or more components to produce a stable, isolable compound.For example, a first component and a second component may react to formone reaction product comprising the first component and the secondcomponent joined by a covalent bond. That is, the term “reacting” doesnot refer to the interaction of solvents, catalysts, bases, ligands, orother materials which may serve to promote the occurrence of thereaction with the component(s). A “stable, isolable compound” refers toisolated reaction products and does not refer to unstable intermediatesor transition states.

In the compounds and compositions of the invention, the term “alkyl”refers to the radical of saturated aliphatic groups, includingstraight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkylsubstituted alkyl groups. In some embodiments, a straight chain orbranched chain alkyl may have 30 or fewer carbon atoms in its backbone,and, in some cases, 20 or fewer. In some embodiments, a straight chainor branched chain alkyl may have 12 or fewer carbon atoms in itsbackbone (e.g., C₁-C₁₂ for straight chain, C₃-C₁₂ for branched chain), 6or fewer, or 4 or fewer. Likewise, cycloalkyls may have from 3-10 carbonatoms in their ring structure, or 5, 6 or 7 carbons in the ringstructure. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, cyclobutyl, hexyl, cyclochexyl, and the like.

The term “heteroalkyl” refers to an alkyl group as described herein inwhich one or more carbon atoms is replaced by a heteroatom. Suitableheteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like.Examples of heteroalkyl groups include, but are not limited to, alkoxy,amino, thioester, and the like.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

The terms “heteroalkenyl” and “heteroalkynyl” refer to unsaturatedaliphatic groups analogous in length and possible substitution to theheteroalkyls described above, but that contain at least one double ortriple bond respectively.

As used herein, the term “halogen” or “halide” designates —F, —Cl, —Br,or —I.

The terms “carboxyl group,” “carbonyl group,” and “acyl group” arerecognized in the art and can include such moieties as can berepresented by the general formula:

wherein W is H, OH, O-alkyl, O-alkenyl, or a salt thereof. Where W isO-alkyl, the formula represents an “ester.” Where W is OH, the formularepresents a “carboxylic acid.” The term “carboxylate” refers to ananionic carboxyl group. In general, where the oxygen atom of the aboveformula is replaced by sulfur, the formula represents a “thiolcarbonyl”group. Where W is a S-alkyl, the formula represents a “thiolester.”Where W is SH, the formula represents a “thiolcarboxylic acid.” On theother hand, where W is alkyl, heteroalkyl, aryl, or heteroaryl, theabove formula represents a “ketone” group. Where W is hydrogen, theabove formula represents an “aldehyde” group.

The term “aryl” refers to aromatic carbocyclic groups, optionallysubstituted, having a single ring (e.g., phenyl), multiple rings (e.g.,biphenyl), or multiple fused rings in which at least one is aromatic(e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).That is, at least one ring may have a conjugated pi electron system,while other, adjoining rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls and/or heterocyclyls. The aryl group may beoptionally substituted, as described herein. “Carbocyclic aryl groups”refer to aryl groups wherein the ring atoms on the aromatic ring arecarbon atoms. Carbocyclic aryl groups include monocyclic carbocyclicaryl groups and polycyclic or fused compounds (e.g., two or moreadjacent ring atoms are common to two adjoining rings) such as naphthylgroups. In some cases, the

The terms “heteroaryl” refers to aryl groups comprising at least oneheteroatom as a ring atom.

The term “heterocycle” refers to refer to cyclic groups containing atleast one heteroatom as a ring atom, in some cases, 1 to 3 heteroatomsas ring atoms, with the remainder of the ring atoms being carbon atoms.Suitable heteroatoms include oxygen, sulfur, nitrogen, phosphorus, andthe like. In some cases, the heterocycle may be 3- to 10-membered ringstructures or 3- to 7-membered rings, whose ring structures include oneto four heteroatoms. The term “heterocycle” may include heteroarylgroups, saturated heterocycles (e.g., cycloheteroalkyl) groups, orcombinations thereof. The heterocycle may be a saturated molecule, ormay comprise one or more double bonds. In some case, the heterocycle isa nitrogen heterocycle, wherein at least one ring comprises at least onenitrogen ring atom. The heterocycles may be fused to other rings to forma polycylic heterocycle. The heterocycle may also be fused to aspirocyclic group. In some cases, the heterocycle may be attached to acompound via a nitrogen or a carbon atom in the ring.

Heterocycles include, for example, thiophene, benzothiophene,thianthrene, furan, tetrahydrofuran, pyran, isobenzofuran, chromene,xanthene, phenoxathiin, pyrrole, dihydropyrrole, pyrrolidine, imidazole,pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, oxazine, piperidine, homopiperidine(hexamnethyleneimine), piperazine (e.g., N-methyl piperazine),morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, other saturated and/or unsaturated derivativesthereof, and the like. The heterocyclic ring can be optionallysubstituted at one or more positions with such substituents as describedherein. In some cases, the heterocycle may be bonded to a compound via aheteroatom ring atom (e.g., nitrogen). In some cases, the heterocyclemay be bonded to a compound via a carbon ring atom. In some cases, theheterocycle is pyridine, imidazole, pyrazine, pyrimidine, pyridazine,acridine, acridin-9-amine, bipyridine, naphthyridine, quinoline,benzoquinoline, benzoisoquinoline, phenanthridine-1,9-diamine, or thelike.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula: N(R′)(R″)(R′″) wherein R′, R″, andR′″ each independently represent a group permitted by the rules ofvalence. An example of a substituted amine is benzylamine.

Any of the above groups may be optionally substituted. As used herein,the term “substituted” is contemplated to include all permissiblesubstituents of organic compounds, “permissible” being in the context ofthe chemical rules of valence known to those of ordinary skill in theart. It will be understood that “substituted” also includes that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. In some cases, “substituted” maygenerally refer to replacement of a hydrogen with a substituent asdescribed herein. However, “substituted,” as used herein, does notencompass replacement and/or alteration of a key functional group bywhich a molecule is identified, e.g., such that the “substituted”functional group becomes, through substitution, a different functionalgroup. For example, a “substituted phenyl group” must still comprise thephenyl moiety and can not be modified by substitution, in thisdefinition, to become, e.g., a pyridine ring. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described herein. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms.

Examples of substituents include, but are not limited to, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromaticmoieties, —CF₃, —CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, halide,alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido, acyloxy,aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl,arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl,-carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl,arylalkyloxyalkyl, and the like.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

EXAMPLES Example 1

The following example describes a procedure for the TBS-protection ofdihydroxyacetone (Preparation of Compound 2), as described in Sodeoka etal., J. Am. Chem. Soc. 1990, 112, 4906, the contents of which areincorporated herein by reference. To a solution of dihydroxyacetone 1(250.00 g, 2.78 mol) and imidazole (472.34 g, 6.94 mol; 2.5 equiv) inDMF (1250 mL) TBS-Cl (1045.70 g, 6.94 mol; 2.5 equiv) was added overabout 40 min between 0 to 30° C. Then, the mixture was stirred at roomtemperature until dihydroxyacetone was disappeared (typical reactiontime is 4 to 5 hours. Reaction progress was monitored by TLC). Aftercompletion of the reaction, ice-water (1500 mL) was added to thereaction mixture and extracted with ethyl acetate (1500 mL). The aqueouslayer was separated and organic layer was washed with water (1500 mL),then 20% NaCl aq. (1500 mL). The organic layer was evaporated to drynessand the residue was purified by distillation (bp. 135-138° C. at 3 mmHg)to give 2 as colorless oil (849.83 g, 96% yield).

Example 2

Compound 4 was synthesized according to the procedure described inBarbas et al., Org. Lett. 2007, 9, 3445, with slight modifications forlarge scale synthesis. A solution of (S)-glyceraldehyde 3 was preparedaccording to method described in U.S. Publication No. 2007/0073068, andused without purification. The solution of (S)-glyceraldehyde 3 (100 g(assumed net quantity), 768.4 mmol) and 2 (489.63 g, 1536.8 mmol; 2.0equiv) in N-methylpyrolidone (142.5 mL) and water (7.5 mL),O-tert-butyl-L-threonine (26.93 g, 153.7 mmol; 0.2 equiv) was stirred atroom temperature until 3 was no longer detectable by TLC (reaction timewas about 24-72 hours and yield was about 70-95%; however, this may varydue to the quality and/or solubility of catalyst). This reaction mixturewas diluted with n-hexane (2000 mL) and washed with water (1000 mL),water (500 mL), water (500 mL), 0.1M HCl aq. (500 mL), 5% NaHCO₃ aq.(500 mL), and 10% NaCl aq. (500 mL). The organic layer was evaporated todryness and the residue was purified by silica gel column chromatography(silica gel 2 kg; n-hexane/ethyl acetate=200/1 (4020 mL), 100/1 (4040mL), 50/1 (4080 mL), 20/1 (4200 mL), 10/1 (4400 mL), 4/1 (5000 mL) togive 4 as colorless oil (258.62 g, 75% yield).

Excess TBS-protected dihydroxyacetone 2 was recovered as colorless oil(282.00 g, 58% based on the initial amount), and can be re-used afterdistillation (90% yield).

Also, excess O-tert-butyl-L-threonine was also recovered byconcentrating the 1st to 3rd aqueous layers and adding 2-PrOH (500 mL)to the residue. The mixture was stirred for 10 hours at roomtemperature, upon which a precipitate formed. The precipitate wasfiltered and washed with 2-PrOH to give O-tert-butyl-L-threonine aswhite powder (27.06 g, 53%).

Example 3

The following example describes the synthesis of compound 5. To asolution of aldol product 4 (238.46 g, 531.4 mmol) in acetone (1900 mL)and water (2.3 mL) 70% HClO₄ (7.63 g, 53.14 mmol) was added at 0° C. andstirred at the same temperature for 1.5 hour. The reaction mixture wasquenched with 28% NH₄OH (7.4 mL, 53.14 mmol). A 1M tetrabutyl-ammoniumfluoride in THF solution (1062.8 mL, 1062.8 mmol, 2 equiv) was thenadded, and the mixture was stirred for 9 hours at room temperature.After removal of solvent, the residue was diluted with ethyl acetate(2400 mL) and washed with water (1200 mL) and 20% NaCl aq. (1200 mL).The aqueous layers were reextracted with ethyl acetate (2400 mL), andthe combined organic layers were dried over anhydrous magnesium sulfate.The solvent was evaporated dryness and the remaining residue waspurified by silica gel column chromatography (silica gel 1 kg;n-hexane/ethyl acetate=20/1 (4200 mL), 2/1 (3000 mL), 1/1 (4000 mL)) ato give white powder (130.15 g. 94.1%), which contained about 10-20%impurities. To this powder n-hexane (1440 mL) was added and refluxeduntil powder was dissolved. The solution was gradually cooled to 0° C.,upon which a precipitate formed. The precipitate was filtered and washedwith cold n-hexane (240 mL) to give ent-Shi alcohol 5 as white powder(87.07 g, 63%).

Example 4

The following example describes the preparation of ent-Shi ketone 6. Toa solution of Shi alcohol 5 (187.00 g, 718.5 mmol) in CHCl₃ (655 mL) andpurified water (655 mL) RuCl₃.H₂O (4.47 g, 21.6 mmol, 3 mol %), NaIO₄(230.51 g, 1077.7 mmol, 150 mol %), BnNEt₃Cl (8.18 g, 35.9 mmol, 5 mol%) and K₂CO₃ (14.89 g, 107.8 mmol, 15 mol %) were added and the mixturewas refluxed for 1.5 hours with vigorous stirring. After startingmaterial was disappeared, the mixture was cooled to room temperature. Tothis mixture 2-PrOH (47 mL) was added and stirred for 1 hour, then themixture was filtered with celite and the residue was washed with CH₂Cl₂(935 mL). The aqueous layer of the filtrate was removed and the organiclayer was washed with 1M HCl aq. (560 mL), water (560 mL), 20% Na₂SO₃aq. (560 mL), and 10% NaCl aq. (560 mL). The aqueous layers werereextracted with CH₂Cl₂ (560 mL). The combined organic layer was driedover anhydrous magnesium sulfate and concentrated to dryness. To theresidue n-hexane (1580 mL) was added and the mixture was refluxed for0.5 hours. Then the mixture was filtered and washed with hot n-hexane(300 mL). The filtrate was gradually cooled to −20° C. without stirringand stand for overnight. The precipitate was filtered and washed withcold n-hexane (370 mL) to give ent-Shi ketone 6 as a colorless needle(163.23 g, 88%).

What is claimed:
 1. A compound of the Formula (I):

wherein: R¹ and R² can be the same or different and each can behydrogen, alkyl, or aryl, provided that when one of R¹ and R² ishydrogen, the other is alkyl or aryl; R³ is a protecting group; R⁴ is aprotecting group that can be removed in the presence of an acid; and R⁵,R⁶, R⁷, and R⁸ can be the same or different and each can be hydrogen,alkyl, or aryl, wherein the protecting group is trimethylsilyl (TMS),tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS),[2-(trimethylsilyl)ethoxy]methyl (SEM), trimethylsilyl triflate,triethylsilyl triflate, or tri-t-butylsilyl triflate.
 2. The compound ofclaim 1, wherein the compound has the following structure,


3. A compound of the Formula (II):

wherein: R¹ and R² can be the same or different and each can behydrogen, alkyl, or aryl, provided that when one of R¹ and R² ishydrogen, the other is alkyl or aryl; and R⁵, R⁶, R⁷, and R⁸ can be thesame or different and each can be hydrogen, alkyl, or aryl.
 4. Thecompound of claim 3, wherein the compound has the following structure,